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Lower oxygenation targets for critically ill COVID patients with severe hypoxemia led to significantly more days alive and off life support, a randomized trial conducted at nearly a dozen intensive care units (ICUs) in Europe found.

At 90 days, patients assigned to a partial pressure of arterial oxygen (PaO₂) target of 60 mm Hg spent 80 days alive and without life support versus 72 days for those whose clinicians aimed for a higher (90 mm Hg) oxygenation target (P=0.009), a difference that narrowed but remained significant after adjusting for certain baseline variables, reported Bodil Rasmussen, MD, PhD, of Aalborg University Hospital in Denmark, and colleagues.

The benefit was mainly driven by reduced use of mechanical ventilation, though 90-day mortality was numerically lower in the group assigned to the lower oxygenation target as well (30.2% vs 34.7%, P=0.18), according to findings from the HOT-COVID trial published in .

"Targeted oxygenation in critically ill patients in the ICU has been extensively investigated in recent years, but there remains uncertainty about the effects of higher vs lower oxygenation strategies," the researchers explained, adding that the results in non-COVID patients may not be applicable, given COVID pneumonia's distinct pulmonary pathophysiology.

"Establishing a safe oxygenation strategy in COVID-19 patients may ensure that supplemental oxygen is dosed for optimal effect and minimal harm while allowing efficient use of available oxygen supplies, ICU beds, and ventilators," wrote Rasmussen and co-authors.

The current findings do align, however, with from the HOT-ICU trial that suggested a more conservative oxygenation target may be beneficial for critically ill patients with COVID-19 in reducing the use of mechanical ventilation.

In contrast, "no differences in ventilator-free days in non-COVID-19 patients were found between lower and higher oxygenation targets in the ICU-ROX trial, the HOT-ICU trial, and the trial, or among lower, intermediate, and higher oxygenation targets in the trial," the investigators noted. Moreover, "the recent Oxy-PICU trial observed a lower duration of life support or incidence of death among pediatric ICU patients with a conservative oxygenation target vs a liberal oxygenation target."

"Could higher oxygen targets help in some ways (e.g., greater oxygen delivery) but hurt or harm patients in other ways, thereby negating any advantage?" posited Richard Schwartzstein, MD, of Harvard Medical School in Boston, in an .

"High levels of supplemental oxygen resulting in a fraction of inspired oxygen greater than 0.6 have been shown to contribute to lung injury," he continued. "In addition, high concentrations of oxygen may lead to the formation of reactive oxygen species, which may cause harm throughout the body, including inflammation, bronchial epithelial injury, and disruption of mitochondrial respiration."

Schwartzstein suggested too that high oxygen targets could play a role in the pulmonary fibrosis that sometimes develops in patients who survive acute hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS).

"It is possible that some of this damage and associated abnormalities in pulmonary function testing and decrement in quality of life in this group may be due to lung toxicity associated with use of high oxygen targets during the acute illness," he said.

Primary data analysis for the (Handling Oxygenation Targets in COVID-19) trial included 697 adult patients with COVID-19 and severe hypoxemia who were randomized 1:1 to the lower or higher oxygenation groups at 11 ICUs across Denmark, Switzerland, and Norway.

Severe hypoxemia was defined as requiring supplemental oxygen with a flow of at least 10 L/min in an open system or either invasive or noninvasive mechanical ventilation. Patients enrolled were expected to need supplemental oxygen for at least 24 hours in the ICU and have a functioning arterial line for PaO₂ monitoring. Regardless of randomization, clinicians made decisions regarding the devices used for oxygen supplementation, as well as ventilator settings.

Median participant age was 66 years, and 68% were men. More than 70% of the patients had pneumonia and over 40% had ARDS. Coexisting illnesses included ischemic heart disease in 10%, active hematologic malignancy in 9%, and chronic obstructive pulmonary disease in 7%.

Median PaO₂ at baseline was 70 mm Hg and 71 mm Hg in the lower and higher oxygenation groups, respectively, while median arterial oxygen saturation (SaO₂) was 94% in both groups. About a fourth of patients were on invasive mechanical ventilation at enrollment, 13% were on noninvasive ventilation or continuous positive airway pressure, and more than 60% received oxygen in an open system.

Examining other elements of the primary outcome showed a greater number of days without mechanical ventilation in the lower versus higher oxygenation group (median 71 vs 62), as previously noted, but a similar number of days without circulatory support (86 vs 84) and without kidney replacement therapy (90 days for both groups).

Secondary outcomes were not significantly different between groups, though point estimates for days alive and out of the hospital at 90 days favored the lower oxygenation target (median 59 vs 48). Serious adverse-event rates were similar, at 47.5% in the lower-target group and 51.4% in the higher-target group.

An important limitation, noted Rasmussen and co-authors, was that the trial was stopped early for slow enrollment during the study period (August 2020 to March 2023), likely due to ICU patients with severe hypoxemia from COVID being less frequent as the pandemic slowed. Other potential limitations included missing data on virus variants and COVID-specific treatments.

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